Micro RNAs (miRNAs) are conserved among diverse organisms, and are involved in essential biological processes throughout the life span of an organism (Esquela-Kerscher and Slack, 2006). In particular, miRNAs have been implicated in regulating cell growth, and cell and tissue differentiation, cellular processes that are associated with development.
Let-7 miRNAs function as gene silencing molecules that regulate the expression of protein-coding genes that comprise a let-7 target sequence. Let-7 miRNAs function to repress the expression of genes at the posttranscriptional level.
Let-7 is itself regulated by post-transcriptional modifications, for example, by the pluripotency factor LIN28 or by c-MYC. For example, LIN28 expression is reciprocal to that of mature let-7 and LIN28 selectively binds the primary and precursor forms of let-7, thereby inhibiting the processing of pri-let-7 to form the hairpin precursor. The binding of LIN28 to let-7 is thought to be facilitated by an interaction between the conserved loop sequence of a primary let-7 family member and an RNA-binding domain of a LIN28 protein. In addition, let-7 miRNAs in mammals have also been shown to regulate LIN28, indicating that let-7 may reciprocally enhance its own level by repressing LIN28, its negative regulator.
Distinctive expression patterns of miRNA have been shown in the hearts of normal mice and mice that suffered from heart disease (van Rooij et al. (2006) Proc. Natl. Acad. ScL, Vol. 103(48):18255-18260). For example, specific miRNAs were differentially regulated in mice induced to have pathological hypertrophy, or in response to constitutive activation of calcineurin, a stress-inducible mediator of the hypertrophic response. Importantly, several of these microRNAs were also dysregulated in failing human hearts, suggesting they established a diagnostic molecular signature for cardiac pathogenesis.